Synergistic antiseptic compositions

ABSTRACT

COMPOSITIONS POSSESSING ANTIBACTERIAL ACTIVITY THROUGH THE EFFECT OF SYNERGISTIC MIXTURES OF 2,2&#39;&#39;-METHYLENE-BIS-(4, 6-DICHLOROPHENOL)-DI-(N-METHYLCARBAMATE) AND 4,4&#39;&#39; - DICHLORI-3-TRIFLUOROMETHYL CARBANILIDE.

Aug. 29, mz D, TABER' 'n AL 3,687,856

SYNERGISTIC ANTISEPTIC COMPOSITIONS LEO A, RAPHAEL/AN Mara? o.rABER ETAL 3,687,856

'sYNERGIsTIc ANTISEPTIC courosr'rrous Aug. 29, 1912 2 Sheets-Sheet 2 Filed July 20, 1970 FIG. 2

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M/c PPM ,/NVE N TORS DAV/o TABEA LEO A.y RAPHAEL/AN SYM@ u? United States Patent O 3,687,856 SYNERGISTIC ANTSEPTIC COMPOSHTIONS David Taber, Evanston, and Leo A. Raphaelian, Wilmette, Ill., assignors to Armour-Dial, Inc., Chicago,

Filed July 20, 1970, Ser. No. 56,271 Int. Cl. Clld 9/50 U.S. Cl. 252--107 6 Claims ABSTRACT F THE DISCLOSURE Compositions possessing -antibacterial activity through the effect of synergistic mixtures of 2,2methylenebis(4, -dichlorophenol)di-(Nmethylcarbamate) and 4,4 dichloro-3-triluoromethyl carbanilide.

The present invention relates to antiseptic compositions which possess synergistic activities through the eect of mixtures of antibacterial agents. More specifically the present invention relates to a mixture of either triclocarban or 4,4'dichloro3-triuoromethyl carbanilide and a di-methylcarbamate, 2,2methylenebis (4,6 dichlorophenol)di(N-methylcarbamate) having the formula:

l ll oiJNHCHa OCNHCH,

ol- CH c1 I o1 o1 Antiseptic or antibacterial agents have been used in soaps and other detergent and cosmetic cleansing preparations for a considerable period of time. One of the most widely used types of such agent has been certain halogenated bisphenols, such as those described in U.S. Pat. 2,535,077, and particularly hexachlorophene[2,2'methyl ene-bis (3,4,6-trichlorophenol) The past decade has seen major improvements in antibacterial systems for cleaning compositions like soap, such as by the introduction of new antibacterial agents and the introduction of synergistic antibacterial systems. However, the number of compounds and systems which have been developed and are suitable from technical, safety and economic points of view has been really quite small. In order for a new -antibacterial agent or system to become part of a successful product such as a toilet soap, the compounds must possess broad spectrum antibacterial activity. Such antibacterial activity must be maintained in the presence of soap or other cleansing agents. Chemical stability in the presence of the cleansing composition must be maintained, as well as nonreactivity with the other cornponents of the cleansing composition such as perfumes, antioxidants, brighteners and the like. `In addition, the product must evidence mildness and safety for general use in the finished product.

Thus relatively few antibacterial agents or bacteriostats and systems have been found which meet all of the above requirements.

At the present time it is estimated that over 46% of all consumer dollars spent annually in the United States on toilet soap is on antibacterial and deodorant soaps. The

Patented Aug. 29, 1972 most important commercially used bacteriostats for use in such cleansing compositions as soap are hexachlorophene, TCC (triclocarban) or 3,4,4trich1orocarbanilide, TBS (3,4,5tribromosalicylanilide), and 4,4dichloro3 tn'- tluoromethyl carbanilide. While these compounds have in general excellent properties and are widely used, they suffer certain drawbacks. Hexachlorophene is somewhat sensitive to sunlight. The substituted ureas may be unstable in alkali media at elevated temperatures.

In efforts to play down the drawbacks of known and effective antibacterial agents, recent attention has been focused upon the development of synergistic bacteriostatic systems. The term synergistic activity as applied herein means an antibacterial effect which is greater in combination than the sum of the antibacterial effects of the separate components. It must be recognized that the occurrence of synergistic activity is highly unexpected and unusual, since the fact that a particular compound may exhibit synergism with a certain other compound generally does not carry over to additional compounds even though they may have similar structures. Further synergistic activity is generally quite limited even as to the ratios and proportions of the individual ingredients exhibiting synergism. An example ofknown synergism may be found in the Casely and Noel U.S. Pat. 3,177,155 disclosing synergistic binary antibacterial systems comprising mixtures of certain isomeric trihalogenated carbanilides, partcularly TCC, with a' number of halogenated bisphenols and alkylated halogenated bisphenols, particularly hexachlorophene. The discovery of such synergism was extremely important in providing soap manufacturers with the ability to not only provide cleansing compositions having a high level of antibacterial activity, but also to maintain such activity with a greatly reduced concentration of antibacterial agents. The latter point is of further importance in allowing the substantial decrease of the amount of hexachlorophene employed in the antibacterial composition, thereby greatly reducing the tendency of the composition to discolor upon prolonged exposure to sunlight.

In accordance with the present invention, it has been found that mixtures of either triclocarban or 4,4dichloro 3triuoromethyl carbanilide and 2,2'methylenebis(4,6 dichlorophenol)di(N-methylcarbamate) exhibit synergistic antibacterial activity, and that this activity is maintained unimpaired when such mixtures are incorporated into various cleansing compositions such as soap and other detergent and cosmetic preparations.

It is therefore an object of the present invention to provide antibacterial compositions which include as antibacterial agents a synergistic combination of triclocarban and 2,2methylenebis(4,6-dichlorophenol) di (N- methylcarbamate Another object of this invention is to provide antibacterial compositions which include as antibacterial agents a synergistic combination of 4,4'dichloro3tri iluoromethyl carbanilide and 2,2methylene-bis(4,6-dichlorophenol) -di- (N-methylcarb amate) It is a further object of this invention to provide antibacterial agents which are effective in soap and in other detergent and cosmetic mediums.

It is still another object of this invention to provide antibacterial compositions which are effective over relatively wide ratios for proportions of the antibacterial ingredients. Other objects and advantages and a fuller understanding of our invention will become apparent from 'the ensuing description and examples.

In a specific embodiment, our invention may be exemplied by a soap composition containing as the antibacterial agent a synergistic mixture of either (A) triclocarban or (B) 4,4-dichloro-3-trifluoromethyl carbanilide and (C) 2,2 methylene-bis (4,6-dichlorophenol)-di-(N-methylcarbamate) and wherein the ratio of A to C present in the soap in parts by weight is about 1 to 41.5 to about 1.94 to 1 and wherein the ratio of B to C in the soap in parts by weight is about l to 40 to about 4.91 to l.

It is found that when components A or B and C of the synergistic mixtures as set forth above are used together, germicidal effects are achieved which are substantially greater than the mere total of the individual effects of the individual ingredients. Such effects are important in cases where it is desirable to increase the activity of the known bacteriostat ingredient without employing higher concentrations. Such effects are also important in cases where it is desirable to reduce the total concentration of the antibacterial agents lwhile at the same time maintaining a desired level of antibacterial effect, or to reduce the concentration of the known bacteriostat, thereby lowering the incidents of drawbacks to the use of that bacteriostat in the product while maintaining high antibacterial effectiveness.

The present invention is still further important in that the above synergistic phenomenae occur even at the high pH conditions existing in detergent formulations such as soap.

The term soap refers to the water-soluble ammonium, phosphorus, metallic, or organic base (such as alkyl or alkoxy-alkyl containing up to about 9 carbon atoms) salts of various fatty acids or long chain synthetic acids wherein long chain refers to aliphatic radicals containing from about 12 to 22 carbon atoms. Such aliphatic radicals may be principally dodecyl, tetradecyl, hexadecyl, octadecyl; and the fatty acids may be chiefly lauric, oleic, stearic and palmetic acids. As used in this description, the term is intended to cover all products in which soap is a major constituent, for example bar, flake, powder, gel and liquid soap; shaving cream; toothpaste; facial and cleansing cream; and the like.

Further the soap ingredient may be partially, substantially or completely replaced with anionic type and nonionic type synthetic detergents. The anionic type synthetics suitable for use in the present invention can be described as those detergents having pronounced cleansing power and including in their molecular structure an alkyl radical containing from 6 to 18 carbon atoms and a sulfonic acid or sulfuric acid ester radical. Either organic base, ammonium, sodium or potassium salts of such anionic type detergents can be used. Principal types of detergents falling within this category are illustrated by alkyl-aryl sulfonates such as sodium or potassium dodecyl benzene sulfonate, sodium or potassium octadecyl benzene sulfonate, and sodium or potassium octyl naphthalene sulfonate; the alkyl sulfates such as sodium or potassium salts of dodecyl, hexadecyl, and octadecyl sulfates; the sulfonated fatty acid amides such as sodium or potassium salts of the oleic acid amide of methyl taurine; and the sulfonated monoglycerides such as the mono-coconut oil fatty acid ester of sodium 1,2-hydroxypropane-3-sulfonate.

Suitable nonionic type synthetic detergents for use in the present invention can be described as those detergents which do not ionize in solution but owe their water-solubility to un-ionized polar groups such as hydroxy, oxyethyl or other linkages. :Principal types of detergents falling Within this category are illustrated by the polyoxyethylene ethers of the higher fatty alcohols and alkyl phenols; the polyethylene glycols of fatty acid; fatty alkylol amide condensation products; polymers of ethylene and propylene oxides; compounds formed by the addition of propylene oxide to ethylene diamine followed by addition of ethylene oxide; fatty acid ethylene oxide condensation products; condensation products of ethylene oxide and a fatty acid ester of a polyhydric alcohol or sugar; and the detergents prepared by heating together a higher fatty acid with a diethanolamine. Exemplary examples of such synthetic nonionic detergents suitable for the purpose of the present invention are ethylene oxide-tall oil fatty acid reaction products; isooctyl phenol-ethylene oxide reaction products, propylene oxide-ethylene oxide reaction products; and combinations of isooctyl phenol-ethylene oxide with coconut oil or the like fatty acid ethylene oxide reaction products.

Relatively small amounts of the components of our synergistic mixtures are sufficient for the increased antibacterial effects in the detergent product. Satisfactory results can be obtained when the combined weights of the above three components are from 0.10% to 5.0% of the total weight of the detergent composition. A preferred range is a weight concentration of about 0.21% to 4.2% and an especially preferred product is one containing soap and 0.5 to 3% combined weight of the above three components, by weight of the composition. It should be understood that even concentrations below the ranges set forth above will provide some degree of antibacterial effects, and a substantially higher concentration than those referred to will also give satisfactory results, although there are economic and other practical considerations which limit the desirability of greater amounts of the antibacterial ingredients in the soap or other medium.

As indicated above, the preferred ratios of the 4,4di chloro-3 tri-lluoromethyl carbanilide to the di-methylcarbamate is about 1 to about `4.91 parts of the carbanilide to about 20 to 1 parts of the di-methylcarbamate; and the preferred ratio of the triclocarban to the di-methylcarbamate is about 1 to about 1.94 parts of the triclocarban to about 41.5 to l parts of the di-methylcarbamate.

The synergistic combination of the 2,2-methylenebis- (4,6-dichlorophenol) -di-(N-methylcarbamate) and either triclocarban or 4,4dichloro3-trifluoromethyl carbanilide can be added to the soap and other detergents by any suitable method which results in a uniform distribution of the agents throughout the entire mass.

Specific examples illustrating our invention are set forth as follows:

EXAMPLE I A convenient and meaningful method of measuring the antibacterial effectiveness of various agents is by means of a modied agar streak method utilizing a 10% soap solution (100,000 p.p.m. of soap) containing the Various test agents. Briefly the test consists of making serial dilutions of the following solution: 10 ml. of a solution containing a specific quantity of the additive(s) in dimethyl formamide is dispersed into 8O ml. of distilled water containing 10 grams of soap. All solutions are maintained at 60 C. until they are dispensed. Aliquots of the dilutions containing concentrations of the bacteriostatic agents ranging from about 0.02 to 10 p.p.m. at 50 C. and thoroughly dispersed into measured amounts of nutrient agar. Plates are poured, allowed to solidify, and streaked with a standard 4 mm. loopful of a 24-hour broth culture of Staphylococcus aureus FDA 209. After incubation for 24 hours at 37 C. teh bacteriostatic end-point is determined. The bacteriostatic end-point, hereinafter called the minimum inhibitory concentration (MIC), represents the minimum concentration in parts per million by weight of the bacteriostatic agent necessary to inhibit all growth of the innoculent organism. No particular minimum inhibitory concentration has been established to determine the usefulness of a bacteriostatic agent; although the lower end-point, the better the bacteriostatic activity and the smaller the amount of the agent necessary to maintain a particular degree of effectiveness.

The soap utilized for these evaluations was a neutral white toilet soap containing about 20% by weight of sodium coco soap and by weight of sodium tallow soap.

Using the modiier agar streak method as set forth above it was determined that a soap solution containing 3% of the 2,2methylenebis(4,6-dichlorophenol)di (N-methylcarbamate) had an end point or MIC or 0.20 p.p.m. It was also determined that a soap solution containing 0.65% of triclocarban had an end point of 0.20 p.p.m. Various proportions of the above solutions were combined to give mixtures that would be expected to give an end-point or MIC of 0.20 p.p.m., if no synergistic activity took place. The amounts used and the end-points (MIC) obtained are set forth in Table I.

merely additive. The curved line B represents the actual MICs of a combination of the components at the varying proportions set forth in the Table. That portion of line B lying between points C and D represents the region in which unexpected or synergistic activity takes place. Thus, there is synergism when the ratio of the di-methylcarbamate to 4,4dichloro3-triuoromethyl carbanilide (parts by weight) is from about 1 to 40 to about 4.91 to 1.

The results set forth in the foregoing examples with respect to a specic soap (20% sodium coco and 80% sodium tallow soap) are obtained with soaps generally.

TABLE I Parts of 3% 0f Percentage of Ratio triclo- MIC Parts of 65% the di-(N- Percentage di-(N- earban to (N- (p.p.m trlclocarban methylcarbatriclocarban methylcarba methyl-carbaversus solution mate) lsolution mate)1 mate) 1 S aureus 100.-.. 0. 650 0. 00 00:1 0. 14 96 4 0. 620 0. 120 5.16z1 0. 12 0. 585 0.300 1. 94:1 0. 09 0. 520 0. 600 1 :1. 16 0. 09 0. 455 0.900 1:1. 98 0. 08 40 0. 390 1. 200 1 :308 0. 07 50 0.325 1. 500 1:4. 62 0.08 60 0.260 1. 800 1:6. 93 0.08 70 0. 195 2.100 l :10. 78 0. O8 80 0. 130 2. 400 1 :18. 50 0. 09 90 0. 085 2.700 1141.5 0.12 100 0. 000 3. 000 1:00 0. 22

N0'1E.-Tested at 0.24022, 0.20, 0.18, 0.16, 0.14, 0.12, 0.10, 0.9, 0.8, 0.07, 0.06, 0.05, 0.04 -I- 0.03.

The results as set forth in the above Table I have been reproduced in graph form on the attached drawings, FIG. 1. In the graph the MICs (ordinate) have been plotted against the concentration (abscissa). Line A represents the expected MIC if the activity of the components were merely additive. The curved line B represents the actual MICs of a combination of the components at the varying proportions set forth in the table. That portion of line B lying between points C and D represents the region in which unexpected or synergistic activity takes place. Thus, there is synergism when the ratio of the di-methylcarbamate to the triclocarban (parts by weight) is from about 1 to 41.5 to about 1.94 to 1.

Using the modifier agar streak method as set forth above it was determined that a soap solution containing 3% of the 2,2 methylene-bis-(4,6-dichlorophenol)-di-(N-methylcarbamate) had an end point or MIC of 0.20 p.p.m. It was also determined that a soap solution containing 0.3% of 4,4'-dichloro-S-triuorornethyl carbanilide had an end point of 0.20 ppm. Various proportions of the above solutions were combined to give mixtures that would be expected to give an end point or MIC of 0.20 p.p.m., if no synergistic activity took place. The amounts used and the end-points (MIC) obtained are set forth in Table 2.

Thus, a fatty acid soap such as sodium laurate, potassium stearate, sodium oleate, and potassium myristate will also produce these results. Furthermore, the synergistic action is independent of the soap medium and will take place in non-detergent media as well as in anionic detergents other than soap and in nonionic detergent systems. At the same time, soap is a system in which the synergistic components are highly effective and useful.

While this invention has been described and exemplified in terms of its preferred embodiments, those skilled in the art will appreciate that variations and modifications may be made without departing from the spirit and scope of the invention.

What is claimed is:

1. Antiseptic compositions consisting essentially of a cleaning composition selected from the group consisting of water-soluble soap, nonionic synthetic detergents and anionic synthetic detergents and containing a synergistic combination of a halogenated carbanilide selected from the group consisting of triclocarbon and 4,4dichloro3 triiiuoromethyl carbanilide, and 2,2methylenebis(4,6 dichlorophenol)di(N methylcarbamate), wherein the ratio of said triclocarbon to said di-(N-methylcarbamate) TABLE 2 Parts of 3% Ratio of the di-(N- carbanilide 2 Parts of 0.3% methyl- Percentage to di-(N- (p.p.m carbanilide 2 carbamate) 1 Percentage di-(N-rnethylmethylversus solution solution carbanilide 2 carbamate) 2 carbamate) l S aureus Nom-Tested at 0.26, 0.24, 0.22, 0.20, 0.18, 0.16, 0.14, 0.12, 0.10, 0.09, 0.08, 0.07, 0.06, 0.05,

0.04, 0.03, 0.02 and 0.01.

The results as set forth in the above Table 2 have been reproduced in graph form on the attached drawings FIG. 2. In the graph the MICs (ordinate) have been plotted against the concentration (absci'ssa). Line A represents in parts by weight is from about 1:41.5 to about 1.9421, and wherein the ratio of said tritluoromethyl carbanilide to said di-(N-methylcarbate) in parts by weight is from about 1:40 to about 4.91.1 and wherein the total concenthe expected MIC if the activity of the components were 75 tration of said halogenated carbanilide and di-(N-methylcarbamate) is from about 0.1% to about 5% by weight of the compoistion.

2. An antiseptic composition according to claim 1 wherein said halogenated carbanilide is triclocarban.

3. An antiseptic composition according to claim 1 5 wherein said halogenated carbanilidc is 4,4dichloro-3 triuoromethyl carbanilide.

4. An antiseptic composition according to claim 1 wherein said cleaning composition is a water-soluble soap.

5. An antiseptic composition according to claim 1 10 References Cited UNITED STATES PATENTS 3,256,200 6/1966 Reller et al 252-106 3,404,207 10/1968 Baker et al 424-300 FOREIGN PATENTS 792,538 3/1958 Great Britain.

LEON D. ROSDOL, Primary Examiner P. E. WILLIS, Assistant Examiner U.S. C1. X.R. 

